The elucidation of HIV/SIV envelope glycoprotein structure/function will continue to be the major focus of the research supported by this grant during the next funding period. The envelope gene products of HIV and SIV play a critical role in the virus life cycle by mediating virus attachment and entry into the CD4-bearing target cell and also play a role in viral pathogenesis by modulating the immune response of the host. Our current studies have provided new insights into the process of viral entry/membrane fusion and have provided evidence for potential interactions between the cytoplasmic domain of these viruses and components of the cell. These novel observations point the way to three broad areas of continued investigation that will be the focus of the proposed funding period. The specific aims of this proposal are: 1. To characterize the role of the tryptophan-rich membrane-proximal (TRMP) domain of gp41 in Env-mediated membrane fusion and glycoprotein incorporation into virus. 2. To analyze the topology and structural requirements of the gp41 membrane-spanning domain for virus assembly and entry. 3. To determine the role of sequences within the cytoplasmic domain (CD) of HIV Env in intracellular transport, and viral pathogenesis: Work from several investigators over the past few years has demonstrated that the cytoplasmic domain of gp41 plays several important roles during virus replication and viral pathogenesis in vivo. This region interacts with domains of Gag during assembly, with cell components during intracellular transport, and appears to modulate the fusogenicity of the Env complex both in the cell and within the virion. Nevertheless, the nature of the signals that mediate these multiple phenotypic effects are incompletely understood, and it is the goal of this proposal to define them through genetic, biochemical and in vivo animal model approaches. [unreadable] [unreadable]